We first demonstrated that injection of AAV-MOR increased MOR immunoreactivity in brain. Using cell culture, we found that AAV-MOR transfection can increase MOR binding and MOR immunoreactivity in 293 cells. These data suggest that treatment with AAV-MOR enhances MOR expression in vivo and in vitro. AAV-MOR or AAV-GFP was then injected into the nucleus Accumbens (NAc) or ventral tegmental area (VTA) of adult C57/BL6 mice. Two weeks after viral infection, animals received methamphetamine or saline for 5 consecutive days. Repeated administration of methamphetamine progressively increased locomotor activity; this sensitization reaction was attenuated by NAc AAV-MOR pretreatment. In contrast, administration of AAV-MOR to VTA enhanced methamphetamine sensitization. AAV-MOR significantly enhanced DA levels in VTA after VTA infection but reduced DOPAC/DA turnover in the NAc after NAc injection. Our data suggest a differential modulation of methamphetamine sensitization by overexpression of MOR in NAc and VTA.